Novel Chemical Process For the Synthesis of Quinoline Compounds

Abstract

Disclosed is a novel, simplified and economic process for making 3-phenylsulphonyl quinolines with an amine group at position 8 of the quinoline ring system, including 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in particular, in the absence of a palladium catalyst. Also disclosed is the crystallization of polymorphic forms of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline.

1 - 13 . (canceled) 
     
     
         14 . A process for the preparation of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, which comprises reacting a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       with a compound having the formula R 1 R 2 NH, in the presence of a base and a solvent; wherein:
 R 1  and R 2  independently represent hydrogen or C 1-6  alkyl, or R 1  and R 2  together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered monocyclic heterocyclyl group which can optionally contain 1 or 2 further heteroatoms selected from O, N and S; and 
 Ph represents an optionally substituted phenyl group. 
 
     
     
         15 . A process according to  claim 14 , wherein the compound of formula (I) is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline, and wherein the process comprises reacting 8-fluoro-3-phenylsulfonylquinoline with an excess of piperazine in the presence of potassium carbonate and n-propanol at a temperature between about 95° C. and about 105° C. 
     
     
         16 . A process according to  claim 14 , further comprising reacting a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein R 3  represents iodine or bromine; with HSO 2 Ph, or a salt thereof, in the presence of a diamine ligand, a metal catalyst, a base and a polar aprotic solvent. 
     
     
         17 . A process according to  claim 16 , wherein the compound of formula (II) is 8-fluoro-3-phenylsulfonylquinoline, and wherein the process comprises reacting 8-fluoro-3-iodoquinoline with HSO 2 Ph sodium salt in the presence of N,N′-dimethylethylenediamine, CuI, diisopropylethylamine and dimethylsulfoxide at a temperature between about 90° C. and about 105° C. 
     
     
         18 . A process according to  claim 16 , which further comprises reacting 8-fluoroquinoline, with an iodinating or brominating agent, which can act as a source of electrophilic iodine or bromine, in the presence of a solvent. 
     
     
         19 . A process according to  claim 18 , which comprises reacting 8-fluoroquinoline with N-iodosuccinimide or N-bromosuccinimide in the presence of acetic acid at a temperature between about 75° C. and about 85° C. 
     
     
         20 . A process according to  claim 14 , which comprises:
 (i) reacting 8-fluoroquinoline with an iodinating or brominating agent, which can act as a source of electrophilic iodine or bromine, in the presence of a solvent to produce a compound of formula (III) and optionally adding a reducing agent once the reaction is completed;   (ii) reacting the compound of formula (III) with HSO 2 Ph or a salt thereof, in the presence of a diamine ligand, a metal catalyst and a polar aprotic solvent to produce a compound of formula (II); and   (iii) reacting the compound of formula (II) with a compound of formula R 1 R 2 NH in the presence of a base and a solvent to produce the compound of formula (I), or a salt thereof.   
     
     
         21 . A process according to  claim 20 , wherein the compound of formula (I) is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline, said process comprising:
 (i) reacting 8-fluoroquinoline with N-iodosuccinimide or N-bromosuccinimide in the presence of acetic acid at a temperature between about 75° C. and about 85° C. to produce 8-fluoro-3-iodoquinoline, and then adding sodium sulphite solution once the reaction is completed;   (ii) reacting 8-fluoro-3-iodoquinoline with benzene sulfinic acid sodium salt in the presence of N,N′-dimethylethylenediamine, CuI, diisopropylethylamine and dimethylsulfoxide at a temperature between about 90° C. and about 105° C. to produce 8-fluoro-3-phenylsulfonylquinoline; and   (i) reacting 8-fluoro-3-phenylsulfonylquinoline with an excess of piperazine in the presence of potassium carbonate and n-propanol at a temperature between about 95° C. and about 105° C. to produce 3-phenylsulfonyl-8-piperazin-1-yl-quinoline.   
     
     
         22 . A process according to  claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in ethyl acetate, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize. 
     
     
         23 . A process according to  claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline in isopropanol, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize. 
     
     
         24 . A process according to  claim 21 , further comprising the step of dissolving 3-phenylsulfonyl-8-piperazin-1-yl-quinoline ethanol, optionally filtering the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline solvent mixture, and then allowing the 3-phenylsulfonyl-8-piperazin-1-yl-quinoline to recrystallize. 
     
     
         25 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein Ph represents an optionally substituted phenyl group or a salt thereof. 
     
     
         26 . A compound according to  claim 25 , which is 8-fluoro-3-phenylsulfonylquinoline, or a salt thereof. 
     
     
         27 . A compound of formula (III) 
       
         
           
           
               
               
           
         
       
       wherein R 3  represents iodine or bromine or a salt thereof. 
     
     
         28 . A compound according to  claim 27 , which is 8-fluoro-3-iodoquinoline, or a salt thereof.